Organic sulfonate derivatives of optically active (non-racemic) epoxy alcohols such as (R)- and (S)- glycidol are extremely useful and versatile intermediates in the synthesis of chiral drugs and other compounds having high physiological activity such as beta-blockers. The synthetic utility of such derivatives has been reviewed in Hanson, Chemical Reviews 91(4), 437-473 (1991).
One method known in the art for the preparation of these useful organic sulfonate derivatives is to react an optically active epoxy alcohol which has been previously isolated in pure form with an organic sulfonyl halide in the presence of a tertiary amine to take up the hydrogen halide generated. Such a procedure is described, for example, in Klunder et al., Org. Chem. 54, 1295-1304 (1989), Nakabayashi et al., Bull Chem. Soc. Jpn. 39, 413 (1966), and Chautemps et al., C.R. Seances Acad. Sci., Ser. C, Feb. 26, 1968, pp. 622-624. Practice of this method suffers from the disadvantage that the optically active epoxy alcohol to be reacted must first be obtained in sufficient purity so as to minimize the occurrence of undesired side reactions and to facilitate subsequent purification of the organic sulfonate derivative. Preliminary isolation of the optically active epoxy alcohol in this manner is not easily accomplished, however, due to the fact that many compounds of this type are notoriously unstable and reactive. Significant losses due to polymerization, ring-opening (e.g., hydrolysis or alcoholysis), acid-catalyzed or thermal decomposition, and the like are often encountered during purification of these substances. Recovery of non-crystalline water-soluble epoxy alcohols such as glycidol in high yield is especially difficult to achieve.
Another proposed solution to this problem is to carry the derivatization of optically active epoxy alcohols with organic sulfonyl halides in situ (without isolation of the epoxy alcohol) immediately following an asymmetric epoxidation reaction [see, for example, Gao et al., J. Am. Chem. Soc. 109, 5765 (1987)]. This derivatization method has the disadvantage, however, of providing relatively low isolated yields of the desired sulfonate derivatives when the stoichiometric ratio of epoxy alcohol organic sulfonyl halide is approximately 1:1. Another drawback of this proposed synthetic scheme is that a number of tedious purification or treatment steps before and after the derivatization reaction are still required. Without wishing to be bound by theory, it is believed that these problems are due, at least in part, to competing reactions of the organic sulfonyl halide with other protic species in the asymmetric epoxidation reaction mixture such as unreacted allylic alcohol, unreacted organic hydroperoxide, and the alcohol derived from the organic hydroperoxide. Another problem associated with the in situ derivatization method is that any unreacted organic hydroperoxide present must first be reduced using a reagent such as a trialkyl phosphate. Reductions of this type are extremely exothermic, however. Even under controlled conditions, a slight but significant loss of epoxy alcohol is difficult to avoid, especially on a large scale. Additionally, one must be careful not to use an excess of reducing agent since the sulfonyl halide or the desired organic sulfonate derivative may be reduced, leading to the production of sulfinate ester as a significant by-product.
The development of improved methods whereby organic sulfonate derivatives of optically active glycidol or the like may be obtained in high yield and high optical and chemical purity would therefore be of considerable value.